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CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation

Nature Immunology volume 14, pages 812–820 (2013)Cite this article

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Abstract

Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1β (IL-1β) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-β and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1β production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1β and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.

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Figure 1: CD36-mediated uptake of oxLDL generates intracellular crystals and activates the NLRP3 inflammasome.
Figure 2: CD36-mediated formation of cholesterol crystals and activation of NLRP3 occurs via a lysosomal pathway.
Figure 3: CD36 regulates priming of the NLRP3 inflammasome by oxLDL via TLR4-TLR6.
Figure 4: Inflammasome activity is impaired in atherosclerosis-susceptible mice deficient in CD36 and its signaling partners TLR4 and TLR6.
Figure 5: Uptake of soluble amyloid-β by CD36 induces intracellular NLRP3-activating formation of amyloid.
Figure 6: CD36 regulates the activation of NLRP3 by IAPP.

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Acknowledgements

We thank F. Maxfield (Weill Cornell Medical College) for Lalistat. Supported by the US National Institutes of Health (R01HL117334 and R01AG032349 to K.J.M.; U24 AI082660 to L.M.S. and K.J.M.; R01 AI079198 to L.M.S.; 5R01HL093262-02 and 1R01HL112661-01 to E.L.; and AI083713 to K.A.F. and E.L.) and the American Heart Association (11POST7400075 to F.J.S.).

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Authors and Affiliations

  1. Department of Medicine, The Leon H. Charney Division of Cardiology, Marc and Ruti Bell Program for Vascular Biology and Disease, New York University School of Medicine, New York, New York, USA

    Frederick J Sheedy, Katey J Rayner, Bhama Ramkhelawon, Hasini N Ediriweera & Kathryn J Moore

  2. Institute of Innate Immunity, University of Bonn, Bonn, Germany

    Alena Grebe & Eicke Latz

  3. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Parisa Kalantari, Susan B Carpenter, Douglas T Golenbock, Eicke Latz & Katherine A Fitzgerald

  4. Department of Pediatrics, Laboratory of Developmental Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Christine E Becker & Lynda M Stuart

  5. Isis Pharmaceuticals, Carlsbad, California, USA

    Adam E Mullick

  6. German Center for Neurodegenerative Diseases, Bonn, Germany

    Eicke Latz

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Contributions

F.J.S. designed, did and analyzed experiments; A.G. analyzed cholesterol crystals in atherosclerotic plaques; K.J.R. and H.N.E. assisted with mouse atherosclerosis experiments. P.K., B.R., S.B.C. and C.E.B. assisted with microscopy experiments; A.E.M. provided CD36-specific ASOs and contributed to experimental design; D.T.G., L.M.S., E.L. and K.A.F. contributed to study design, data analysis, and manuscript preparation; and K.J.M. conceived of the study, designed and analyzed experiments and, along with F.J.S., prepared the manuscript.

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Correspondence to Kathryn J Moore.

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Competing interests

A.E.M. is an employee of Isis Pharmaceuticals, a biotechnology company that develops ASO therapies.

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Sheedy, F., Grebe, A., Rayner, K. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol 14, 812–820 (2013). https://doi.org/10.1038/ni.2639

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